Navigating the clinical landscape of artery of Percheron infarction: A systematic review

Introduction Infarction of the artery of Percheron (AOP) is a rare vascular condition where a single arterial branch supplies blood to the thalamic and midbrain regions, leading to neurological deficits. The challenge lies in its often-delayed diagnosis due to its rarity and diverse clinical presentations, necessitating heightened awareness among clinicians for expedited diagnosis and appropriate therapeutic interventions. Materials and methods All relevant studies involving patients diagnosed with infarction of AOP were retrieved from PubMed, Google Scholar, Web of Science, and Scopus. Only human studies that were published in full English-language reports were included. Included in the search were the terms “Artery of Percheron,” “infarction,” “stroke,” and “demarcation”. Age, gender, presenting symptoms, treatment, recovery time, and outcome of patients with AOP infarction were all recorded. Results A systematic review was conducted on a total of 530 articles, out of which 130 articles met the specified requirements. The average age is 59, with men comprising 57.7% of the population. The symptoms reported were visual disturbance in 43.9% of cases and changed mental state in 77.2% of cases. Treatment options include conservative management (85.4%), thrombolysis (11.3%), and other approaches. The optimal age range for recovery is between 41 and 50 years old. Conclusion Our study on acute AOP infarction highlights male predominance, common comorbidities like hypertension and diabetes, and prevalent symptoms including visual disturbance and altered mental state. Early recognition is crucial, with thrombolytic therapy within the critical time window showing promising outcomes. These findings offer insights for enhanced clinical management of AOP infarction.


Introduction
Considering the neurophysiological significance of the thalamus, a rare form of stroke may jeopardize its cerebrovascular blood supply.There exist variations in said vasculature to the brainstem and thalamus.Merely 4-12% of the population has the artery of Percheron (AOP), making it one of the uncommon variations.Gérard Percheron, a French neurologist, originally reported it in 1973.He stated that it originated from the proximal posterior cerebral artery (PCA), which supplies the paramedian thalamus and rostral midbrain with bilateral artery [1].
Bilateral thalamic infarcts precipitated by AOP infarction may or may not involve the midbrain.Research indicates that this accounts for 0.1% of ischemic and 4% of thalamic strokes, respectively, suggesting such a rarity of this cerebrovascular accident [2,3].As the thalamus is involved in a plethora of neurophysiological functions, it may be challenging to diagnose the presentation.Nonetheless, altered consciousness, cognitive decline, and supranuclear vertical gaze palsies are the most common symptoms of AOP infarction [4,5].
Depending on the pathophysiological etiology, the management of AOP infarction varies.Although dependent on the severity of the infarction, the prognosis is generally favorable in terms of mortality and long-term neurological sequalae [6].Thus, the aim of this systematic review is to provide a comprehensive overview of the diagnosis, clinical symptomatology, and management options available for AOP infarction.Additionally, our study represents the most comprehensive review todate of AOP infarction, which was not discussed systematically before.

Methods
Moreover, the data extracted from selected publications underwent a rigorous evaluation encompassing multifaceted variables such as age, gender distribution, employed treatment modalities, and other significant factors shaping the complex landscape of AOP.This comprehensive approach facilitated a nuanced understanding of the intricacies surrounding AOP across various dimensions.
Our systematic review of AOP commenced with a meticulous examination of diverse facets, encompassing patient demographics, etiological variables, clinical presentations, diagnostic methodologies, treatment approaches, and subsequent outcomes.Adhering rigorously to the PRISMA guidelines, our methodology ensured a comprehensive analysis.

Search strategy
To ensure inclusivity, an extensive search spanned four key online databases-PubMed/MEDLINE, Google Scholar, Web of Science, and Scopus-without imposing any timeframe restrictions.A refined set of keywords and Mesh phrases: "Artery of Percheron," "infarction," "stroke," and "demarcation," was tailored to optimize search precision and breadth.
In alignment with our research focus, the review specifically targeted human studies published in the medium of the English language and granting access to full-text content.Articles that did not meet the abovementioned criteria were excluded.

Screening of studies and data extraction
Our screening process commenced with an initial assessment of study titles and abstracts to gauge alignment with our research scope.Subsequently, after eliminating duplicate entries, Two independent authors (O.A. and Y.A.) extracted relevant data from selected studies.The data collected included information such as study design, participant demographics, and the number of participants with respective outcomes and complications.Discrepancies in data extraction were resolved through consensus, and any unresolved disagreements were addressed by involving a third reviewer (O.B.) (Fig. 1).

Data analysis
The data was subjected to analysis, encompassing several variables such as age, gender, presenting symptoms, imaging findings, strategies for treatment, clinical outcomes, and subsequent follow-up.The analysis was done using the SPSS 26.Raw data extracted from studies was used as numeric inputs and accordingly scaled, nominated or ordinated.The frequencies, mean, median and the quartiles were analyzed.The significance of the results was delivered by using the Chi-Square in the cross tables.

Quality assessment
The quality assessment was performed using the JBI Checklist for Case Reports.Each article was screened twice and no article was excluded following the assessment.

Results
Initially, 530 articles were drawn from four databases.After a thorough review of titles, abstracts, and full texts, 130 papers met the inclusion criteria.This study investigated patient-level data from diverse research designs involving 279 individuals diagnosed with AOP infarction (Table 1).
Following corresponding missing data exclusion, SPSS software version 26 was utilized for analyzing documented variables.The mean patient age was 59 years (Table 2), with 158 males constituting 57,7% of the total population.Among the population, 125 patients (46.8%) had hypertension, 56 (21.3%) had diabetes mellitus.
Treatment-wise, 129 (85,4%) were managed conservatively,  Statistical significance via the Pearson Chi-Square test with a (p-value<0,05) indicated several associations: (A) Patients with arterial hypertension and other cardiovascular diseases were inclined to develop severe deficits.(B) Higher risk of developing deficits was found with involvement of the paramedian thalamus more than the midbrain, which tremendously increases with involving both of them.(C) Patients presenting with anisocoria tend to have more deficits at the last follow up than those presented without it.(D) The best age group to recover completely is those between 41 and 50 years old, they have more complete recovery rat than any other group while the worst (Fig. 2).(E) altered consciousness at the time of administration tends to develop more severe symptoms.

Discussion
The classic categorization of the thalamic vascular supply delineated into four distinct territories-namely, anterior, paramedian, inferolateral, and posterior-showcases the complex and overlapping nature of this intricate vascular network within the brain.Gérard Percheron's pivotal 1973 discovery of the AOP introduced a fascinating anomaly within this established framework.Originating from segment one (P1) of the posterior cerebral artery (PCA) and observed in a minority of individuals (approximately 4%-12% of the population).The AOP uniquely supplies both sides of the paramedian thalamus and the upper midbrain through a single shared branch.This underscores the potential interplay and connectivity between the traditionally categorized thalamic territories, highlighting the significance of such rare anatomical variations in understanding the broader thalamic vascular supply [3,7].
Percheron identified four types of paramedian perforating arteries to the thalami (Fig. 3).The first variant (type I), involves the arteries emerging from the proximal segments of both PCAs on each side.The second type (type IIa), occurs when the arteries arise directly from the proximal segment of just one PCA.However, in some people, a single arterial trunk stems off the P1 segment of one of the PCAs and this trunk then divides to supply both thalami and the upper midbrain (type IIb); this is the AOP.Lastly, Type III is defined by the presence of a single arterial arc that links the proximal segments of both PCAs and from this arc, the paramedian thalamic perforating arteries arise [7][8][9].In this study, we elucidated that the type I variant was most prevalent among 81% of the population, while type IIa was observed in only 9.5%.The rarest variant type IIb and type III, were found in just 4.8% of the individuals examined.
Artery of Percheron occlusion results in a Percheron infarction, marked by specific bilateral paramedian thalamic distribution potentially alongside a mesencephalic distribution [10] (Fig. 4).With a relatively small ischemic lesion in the bilateral paramedian thalami, patients with Percheron infarction would present with an apparent lifethreatening event comprising a massive ischemic infarction unless prompt intervention is administered [11,12].Although likely underestimated, the prevalence of AOP is only 0.1% to 2% and 4% to 18% of all and thalamic strokes, respectively [3,13].Similarly, Bogousslavsky analyzed 1000 consecutive patients sustaining their first episode of stroke and found that isolated thalamic infarcts, as a presenting feature, comprised 11% of all strokes in the posterior circulation while midbrain ischemic infarctions constituted 7% only [14].In clinical practice and imaging, Percheron infarction must therefore be considered for its management.A few isolated cases have been reported in clinical practice in the previous decades [12,15].N.A. Lazzaro et al. and Antonio Arauz et al. successively demonstrated the clinical and imaging aspects of Percheron infarction in 37 and 15 cases, respectively [3,13].
Percheron infarction is a catastrophic cerebral vascular due to its impact on the blood supply to the paramedian thalamus and midbrain.Zhihua Xu et al., found that for patients with acute ischemic infarction, the occurrence of Percheron infarction was 0.27% [16].Furthermore, researchers have demonstrated that 0.1%-0.4% of all patients with first episode of acute ischemic stroke sustained a Percheron infarction [3,17,18].Our findings correlate with prior studies in the literature.Percheron infarction, although rare, usually presents with an apparent life-threatening event.However, the initial and subsequent symptoms are variable.Therefore, it is difficult for a neurologist to diagnose this condition in a timely manner with clinical observations alone.Moreover, there is no predilection to sex, race-ethnicity, and age in the reported cases of AOP stroke in the literature [18,19].Our study findings, aligned with those of Garcia-Grimshaw et al., indicate that the characteristics of AOP stroke, including age distribution and gender predominance, may vary based on its etiology [19].Much like Lin (P.C.), our research highlights a wide occurrence of AOP stroke across various age groups, with a notable concentration observed within the 30 to 70-year range [20].Similar to our study, Stamm (B.J.) et al. and Suzuki (K.)et al. found a slight male predominance in patients with AOP stroke, aligning with the general trend observed in prior research [21,22].
In our study, the risk factors for Percheron infarction included hypertension, hyperhomocysteinemia, recent history of smoking, Diabetes Milletus (DM), and hyperlipidemia [3,23].Specifically, among the   [25].These differences might influence the response to variations in region or race.Generally, the most common etiologic factors for Percheron infarction are small vessel disease and cardio-embolism [3,25].Analyzing our findings, 96.1% of the cases were attributed to ischemia, indicating the multifaceted origins of this condition.Contributing factors encompassed perforation (0.4%), stenosis (1.2%), minor arterial disease (0.8%), CVD (including both cardio-embolism and other cardiac-related etiologies) and other factors (1.4%).These factors support the prevalent recognition of small vessel disease, CVD, and ischemia as primary etiological factors in Percheron infarction, highlighting the intricate pathways leading to its occurrence.
Lazzaro et al. identified four distinct ischemic infarction patterns arising from AOP occlusion based on their review of 37 patients, by evaluating clinical presentations and imaging findings.Among their observations, the most common pattern (43%) demonstrated damage to both the paramedian thalami and midbrain, while 38% of the patients exhibited isolated paramedian thalamic injury.In approximately 14% of the cases, damage extended to the anterior thalamic nuclei in addition to the paramedian thalami and upper midbrain.A rarer pattern (5%) depicted bilateral paramedian and anterior thalamic damage without midbrain involvement [13].In our study, the primary site of infarctions was aligned with Lazzaro et al. findings [13], with the paramedian thalamus being the most affected (38,5%), followed by both midbrain and paramedian thalamus involvement (46.9%).Other injury sites were less prevalent, accounting for only 20%.Patients experiencing Percheron infarction encounter diverse initial symptoms.Some individuals exhibit unremarkable and atypical symptoms, like dizziness.On one hand, these subtle symptoms might be overlooked by certain physicians; on the other hand, patients might not prioritize seeking adequate care.Consequently, these circumstances may extend the duration between symptom onset and seeking medical attention.Additionally, accurately determining the precise timing of the ischemic infarction poses a challenge when establishing the thrombolytic therapy window.Furthermore, subsequent symptoms manifest differently in each case.Hence, relying solely on clinical observations renders timely diagnosis impossible, highlighting the necessity for early recognition and immediate imaging for this condition [16].
When suspecting Percheron infarction, prioritizing magnetic resonance imaging-diffusion-weighted imaging (MRI-DWI) sequences becomes crucial due to the clinical relevance of apparent diffusion coefficient (ADC) maps and DWI in timing these infarctions [26,27].Zhihua Xu et al. conducted a study, in 18 cases, that demonstrated a 100% positivity rate for detection and localization of Percheron infarction using MRI-DWI sequence, while computed tomography (CT) exhibited negative results in 50% of the patients [16].This underscores the pivotal role of the DWI-MRI sequence in accurately diagnosing Percheron infarction.Nonetheless, we emphasize the importance of conducting a CT scan upon admission to exclude brain hemorrhage [26,27].Instances reported by Cassourret G et al. and Mecbure Nalbantoglu et al. noted an AOP occlusion in normal initial brain MRIs, including DWI sequences [28,29].Therefore, considering a second MRI may be warranted if a strong clinical suspicion of Percheron infarction persists [16].
Until now, the diagnosis of Percheron infarction depended on lesions in a specific bilateral paramedian thalamic distribution with or without a mesencephalic distribution based on brain imaging.Other etiologies, such as top basilar syndrome, deep cerebral vein thrombosis, Wernicke's encephalopathy, and glioma, should be considered [16].Eva Guy Rodriguez et al. indicated that patient history, specific imaging characteristics, and the presence or absence of lesions outside the thalami aid in narrowing the differential diagnosis [30].
Percheron infarction results from occlusion within the AOP, which is usually not visible on standard magnetic resonance angiography (MRA) scans.Zhiua conducted a study that did not demonstrate the typical AOP image using MRA, but instead found that patients with Percheron infarction lacked the posterior communicating artery (PCoA) on several scans.This absence might suggest a lack of the primary collateralization [16].However, it could also indicate natural variations in the circle of Willis.These variations could exacerbate symptoms when combined with internal carotid artery stenosis [31].Some evidence also suggested that PcoA hypoplasia may contribute to a propensity for thalamic lacunar stroke due to its dominant role in providing collateral supply to the proximal PCA territory [32].However, the presence of anatomic variations like the AOP and PcoA hypoplasia?Could potentially lead to a hemodynamic infarction due to inadequate regional collateral blood flow [16].
Bithalamic stroke is closely linked to the thalamus, pivotal in sleep regulation and arousal maintenance.Interruption of noradrenergic and dopaminergic impulses from the ascending reticular activating system to the thalamus contributes to hypersomnolence post-stroke [34,35].Bilateral thalamic infarcts result in more pronounced sleep-wake disturbances compared to unilateral infarcts [36], often leading to increased sleep needs [35,36].
In this study, 43.9% of our patients presented with visual disturbance and gaze palsy, which resonates with the common bilateral vertical gaze palsy described in previous studies [34][35][36].Moreover, altered mental status was prevalent in 77.2% of our cases, a percentage consistent with the documented high incidence of coma in AOP strokes.However, memory deficits were observed in 5.3% of our cases, which is lower compared to the literature [19,33].Furthermore, less frequent symptoms in our study motor deficits and dyscoordination were found in patients (35.6%) and slurred speech (14.6%).
Understanding the relationship between imaging findings and the diverse clinical presentations of Percheron infarction could significantly improve its recognition and subsequent management.This analysis would play a crucial role in guiding both the diagnosis and the selection of appropriate treatment strategies for this condition, enhancing our comprehension of its complexities and potential complications.
Among cases managed for acute AOP infarction, our findings reveal notable associations with different treatment modalities.Thrombolytic therapy, specifically within a time window of <4.5 to 6 h, demonstrated a substantial link to achieving complete recovery and mild residual deficits during the final follow-up, affirming its status as the most effective treatment for acute AOP infarction [37].This therapy aims to promote recanalization, aligning with the current goal of managing acute AOP occlusion [38].Conversely, conservative management, observed in 85.4% of cases, also showed a significant portion achieving complete recovery [39].A minimal percentage (2.6%) of the patients in our study underwent mechanical thrombectomy, which exhibited a significant correlation with mild residual deficits observed during the last follow-up.The prominence of thrombolytic therapy within the critical time window underscores its efficacy and highlights the importance of prompt intervention in treating infarctions involving the AOP [39].

Conclusion
In conclusion, our study sheds light on acute artery AOP infarction, a rare but clinically significant cerebrovascular condition.Through meticulous analysis of patient-level data from 130 papers involving individuals, we have identified common clinical characteristics, etiological factors, and treatment outcomes.Our findings reveal a male predominance, with hypertension and diabetes mellitus being common comorbidities among the studied population.Symptomatically, visual disturbance, altered mental state, and motor deficits were prevalent presentations, with ischemia, particularly involving the paramedian thalamus, identified as the primary cause.Furthermore, we uncovered significant associations between various factors and the development of severe deficits, emphasizing the importance of early recognition for

Table 1
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Table 1 (
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Table 2
Demographic characteristics of the patients included in the study.

Table 3
Clinical presentation, etiology, and the vascular supply to the thalamus.

Table 4
[24]tment options and follow-up.examined,asubstantialportion of the patients (46.5%) had preexisting hypertension, with the majority being males (57,7%).Furthermore, DM was reported as a risk factor in 56 (21.3%) out of 280 patients.Expanding on the risk factors, Saez et al. highlighted distinct patterns in thalamic strokes across different age groups.They found that in younger patients, cigarette smoking was the primary risk factor.In contrast, for individuals aged 45 and above, hypertension emerged as the predominant risk factor, attributed to its association with atherosclerosis.This observation signifies a shift in prominent risk factors with age, evident across various stroke types, including Percheron infarction[24].
Key: *Combination of thrombolysis and mechanical thrombectomy.O. Atallah et al. patients Our study on Percheron infarction's etiology resonates with diverse perspectives from Arauz et al. and de la Cruz-Cosme et al.Arauz et al. identified small vessel disease as the primary cause [3], while de la Cruz-Cosme et al. emphasized a dual association with cardio-embolism and cardiovascular diseases (CVD), including conditions like stenosis